Citicoline affects proteosome in a dose-dependent manner

Highlights

• 100 nM Citicoline induced 2-fold stimulation of proteasome (R1)
• The activation effect was seen in the range 50 - 100nM and was lost with higher concentrations (R1)
• Citicoline was not able to restore proteasome’s activity in the presence of inhibitor epoxomicin (R1)
• Proteasome can be inhibited or overwhelmed by proteotoxic stress.

Quotes

Therefore, we can state that citicoline, beside behaving as aproteasome inhibitor, also displays a concentration range within which it plays a robust activation role, a property which might extend its therapeutic application also to pathologies wherefore proteasome activity is primarily depressed or overwhelmed by the proteo-toxic stress, such as in some neuro-developmental and neurogenerative diseases. (R1)

the initial activation of the 20S activity is followed, upon further addition of citicoline, by an inhibition of this activity, which greatly expands the potential therapeutic applicability of this molecule.

It clearly envisages the existence of a different class of binding sites, whose occupancy by citicoline molecules counteracts the effect of the first binding cluster of sites, by turning the 20S activity back to that of 20S in the absence of the ligand. It indicates that the binding of citicoline to the second site triggers a competitive inhibition of the 20S activity (R1)

Citicoline possibly increases the pool of capped particles

Thus, the whole set of data suggests that citicoline stimulates the proteolytic burden of the UPS by increasing the pool of capped particles. According to recent advances in the field, these assemblies are thought to deal with clearance of poly-ubiquitinated proteins (R1)

However, additional citicoline administration keeps unaltered, or even increased the activity of free 20S, which is instead considered an efficient actor for the degradation of oxidized-misfolded-natively unfolded proteins.

Remarkably, this phenomenon is already detectable over a time-interval (i.e., 3 h) where no synthesis of novel proteasome particles may have occurred, and even after 24 h of treatment this occurrence appears negligible.

Therefore, citicoline treatment is expected to couple the increase in poly-Ub degrading activity (e.g., that of capped assemblies) without altering the activity on substrates which do not require the Ub-tag (e.g., that of 20S). This is a clear advantage in cells suffering from a proteostasis umbalance. (R1)